Cellular Models for Epigenetic Regulation of Adrenal Steroidogenesis

Presentation Number: MON 394
Date of Presentation: April 3rd, 2017

Hans Kumar Ghayee*1, Richard J. Auchus2 and Sergei G Tevosian3
1University of Florida College of Medicine, FL, 2University of Michigan, Ann Arbor, MI, 3University of Florida, Gainesville, FL

Abstract

Recent whole-genome sequencing efforts powered by international consortium research groups have identified several promising pathways and candidate driver genes in adrenocortical carcinomas. One of the major impediments in converting the wealth of information derived from these whole-genome approaches into treatments is a nearly complete absence of versatile cell culture models that are representative of defined adrenocortical lineages. To capitalize on this genomic data, rational design of human cell lines that faithfully reproduce pre-malignant states and patients’ tumor cells are imperative. The human adrenocortical cell line currently in use, the NCI-H295 and its variations, are derived from a late-stage aggressive carcinoma. As such, these cells are not representative of a specific adrenal lineage and have limitations for studies that aim to define the origin and the progression of adrenal cancer. Adrenal derived precursor cell lines that could be indefinitely cultured in the undifferentiated capacity and converted as needed into defined differentiated states have not been developed. Activation of human telomerase reverse transcriptase (hTERT) is one of the key events recently identified in adrenocortical carcinomas. Our group therefore sought to develop benign adrenal cortical lineages immortalized with hTERT. Adrenal cells obtained from 2 primary tumors were immortalized, but these lines lost steroidogenic capacity in culture. We hypothesized that de-differentiation involves conversion of key steroidogenic genes into inactive chromatin state and might be reversible. Treatment of the immortalized adrenal cells with histone deacetylase (HDAC) inhibitors sodium butyrate and trichostatin A increased expression of key steroidogenic genes, including CYP11A1, 3BHSD, and MCR2). We conclude that the reversible regulation of chromatin states plays an important role in adrenocortical cell differentiation and cancer development.

 

Nothing to Disclose: HKG, RJA, SGT